1. Field of the Invention
The present invention relates to the use of DHEA or at least one of biological precursor thereof or metabolic derivative thereof in or for the manufacture of a composition for topical application to the skin, as a pigmentation regulator for the skin or its superficial growths, especially a depigmenting and/or bleaching agent for the skin, in particular, for the treatment of pigmentation marks.
2. Description of the Background
The color of human skin depends on a variety of factors and, in particular, the seasons of the year, race and sex, and it is mainly determined by the nature and concentration of melanin produced by the melanocytes. Melanocytes are specialized cells which synthesize organized melanin by means of specific organelles, the melanosomes. In addition, at different periods in their life, certain individuals develop darker and/or more colored blemishes on the skin and more especially on the hands and the neck and shoulders, making the skin non-uniform. These blemishes are also due to a large concentration of melanin in the keratinocytes located at the skin surface.
The mechanism for the formation of skin pigmentation, that is to say the formation of melanin, is particularly complex and schematically involves the following main steps:
Tyrosine→Dopa→Dopaquinone→Dopachrome→Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this reaction sequence. It catalyzes the reaction for the conversion of tyrosine into dopa (dihydroxyphenylalanine) by virtue of its hydroxylase activity and the reaction for the conversion of dopa into dopaquinone by virtue of its oxidase activity. This tyrosinase acts only when it is in the mature state, under the action of certain biological factors.
A substance is recognized as being depigmenting if it acts directly on the vitality of the epidermal melanocytes in which melanogenesis takes place and/or if it interferes with one of the steps in the biosynthesis of melanin either by inhibiting one of the enzymes involved in melanogenesis or by becoming intercalated as a structural analog of one of the chemical compounds in the melanin synthesis chain, whereby this chain may then be blocked and thus ensure depigmentation.
The substances most commonly used as depigmenting agents are, more particularly, hydroquinone and its derivatives, in particular its ethers such as hydroquinone monomethyl ether and monoethyl ether. Although they have a certain level of efficacy, these compounds are, unfortunately, not free of side effects on account of their toxicity, which can make them difficult or even hazardous to use. This toxicity arises from the fact that they interfere with fundamental mechanisms of melanogenesis by killing cells which then risk disrupting their biological environment and which consequently force the skin to eliminate them by producing toxins. Thus, hydroquinone is a compound which is particularly irritating and cytotoxic to melanocytes, and whose total or partial replacement has been envisaged by many workers in the field.
It is most particularly sought to use harmless topical depigmenting substances which have good efficacy, with a view to treating regional hyperpigmentations caused by melanocyte hyperactivity, such as idiopathic melasmas, occurring during pregnancy (“pregnancy mask” or chloasma) or during oestroprogestative contraception, localized hyperpigmentations caused by hyperactivity and proliferation of benign melanocytes, such as senile pigmentation marks known as actinic lentigo, accidental hyperpigmentations or depigmentations, possibly due to photosensitization or to post-lesional cicatrization, as well as certain leukodermias, such as vitiligo. For the latter, in which the cicatrizations can result in a scar which gives the skin a whiter appearance and leukodermias, failing being able to repigment the damaged skin, the regions of residual normal skin are depigmented in order to give the skin as a whole a uniform white complexion.
The depigmenting substances also find an application in the bleaching of superficial body growths, in particular of hairs which it may be desirable to lighten in order to make them less visible.
Thus, there is still a need for a novel bleaching agent for human skin or its superficial growths, which acts as effectively as the known agents, but which does not have their drawbacks, i.e. which is non-irritant, non-toxic and/or non-allergenic to the skin and/or its superficial growths.
Conversely, it is known that, in most populations, maintaining a constant hair color is an important aspiration which may either result from aesthetic considerations, or may be justified by the need to overcome a pigmentation anomaly of pathological origin. This is thus the case for canities, or greying of the hair, which is thought to be associated with an autoimmune disease, in particular vitiligo.
Topically-acting pro-pigmenting agents have been proposed before, either in the field of artificial coloration by supplying exogenous dyes, such as DHA, which are supposed to give the skin or superficial body growths a coloration which is as close as possible to their natural coloration, or in the field of natural coloration, by stimulating melanogenesis with or without UV action.
DHEA, or dehydroepiandrosterone, is a natural steroid produced essentially by the corticoadrenal glands. It is known for its anti-ageing properties, associated with its capacity to promote epidermal keratinization (JP-07 196 467) and to combat osteoporosis (U.S. Pat. No. 5,824,671), or alternatively in the treatment of dry skin, on account of its ability to increase the endogenous production and secretion of sebum and to reinforce the skin's barrier effect (U.S. Pat. No. 4,496,556). DHEA is also described in the treatment of obesity and diabetes (WO 97/13500). It has also been proposed to use DHEA sulfate to combat alopecia (JP-60 142 908) and to treat various signs of ageing such as wrinkles, loss of skin radiance and slackening of the skin (EP-0 723 775). However, it has never yet been suggested that DHEA or at least one of its precursors or derivatives might have regulatory activity on pigmentation by acting directly on melanogenesis.